Living along the southern bank of the Savannah River the Yamassee Indians had maintained good relationships with the South Carolina settlers. One of the oldest known Southeastern tribes, the Yamassee controlled much of lower Savannah River inland to the confluence of the Ocmulgee and Oconee. They were widespread but a relatively small group of Creek Indians. According to Ranjel, chronicler of de Soto's travels, the expedition visited the Yamassee town of Altamaha in 1540.

As with most wars, the causes of the Yamassee War begin well before the start of the conflict. Shortly after the completion of Queen Anne's War in 1713, the Creek natives began to get agitated with the English traders on the border of their nation. These traders had made the Indians dependent upon the goods they supplied. Guns, for example, made it easier for the Indians to hunt, increasing the amount of goods they had to trade.

The Creek were unhappy with traders who seemed to be supplementing their slave trade income by occasionally taking a Creek warrior. Other business practices were questioned by the Creek as well. The English would get the Creek Indians intoxicated and then defraud them, cheat them in trade, and take liberties with Creek women (rape was a concept introduced to Native Americans by the English, and later, the Americans).

Members of the Creek tribe complained to South Carolina authorities, who tried to control the traders with a licensing system. The plan failed miserably, so the Creek decided to take matters into their own hands.

First, members of Creek tribes killed all the English traders roaming around the frontier of inland Carolina. Then, on April 15, 1715, Yamassee Indians, supported by the Creek, Catawba, Appalachee, the Governor of New France, Jean-Baptiste Le Moyne, Sieur de Bienville in Mobile, and the Spanish regime in St. Augustine began to attack settlers on a broad front along the southern and western borders of South Carolina.

Settlers began to flee. Some stopped in Charles Town, South Carolina, but many kept going to North Carolina and Virginia.

As the Indians approached Port Royal, the entire town fled. In Charles Town, Governor Charles Craven, who was also a Colonel in the militia, began to establish a perimeter of irregulars and militia. The state was close to collapse - in August of 1715, South Carolina turned to the Cherokees for support.

For many years the Cherokee and Creek had been enemies, so the Cherokee were only too happy to join the war on the side of the South Carolinians. Mush to the surprise of the Cherokee, however, shortly after agreeing to support the English settlers, Creek chiefs approached the Cherokee about joining the Creek in waging war. The Cherokee invited the Creek to a council where the Cherokee killed the Creek chiefs.

Meanwhile, South Carolina forces had advanced from Charles Town and met a large body of Indians at Salkehatchie, sometimes called "Saltcatchers."

The combination of these two events was the turning point of the war.

The Creek/Yamassee thrust into South Carolina halted, and the Indians withdrew. Afraid of retaliation, Creek villages in the area relocated to the west and south and the Yemassee withdrew to the vicinity of St. Augustine, hoping for protection from their Spanish friends. Carolina raiders found the village, routed the residents and destroyed the homes. The remaining Yamassee were absorbed into the Seminole tribe.

The Creek towns withdrew to the Chattahoochee River and the Yuchis moved with them. The people were known as the Lower Creeks. The Upper Creeks were centered on the Coosa and Tallapoosa Rivers to the northeast.